It will be appreciated that a clinician will wish to test lung function for a number of reasons. For example, it can be informative to characterise lung ventilation because such ventilation can be affected by a range of pulmonary disorders. Currently, standard lung function tests can assess a wide range of global variables describing lung physiology but cannot be used to investigate disease regionally within the lung.
Scintigraphy allows for investigation within a particular region of a lung by producing images of a radiation emitting material as it passes through a subject. The technique generally necessitates the inhalation of radioactive substances and is limited by low spatial resolution.
One particular example of a valuable scintigraphic imaging technique is a ventilation/perfusion (V/Q) scan, which comprises two imaging steps. First, the subject is asked to breathe a gas mixture containing a gamma radiation emitter, such as radionuclide xenon or technetium, while images of the subject's chest are recorded using a gamma camera. The resulting images show light areas in lung regions to which the gas has permeated and therefore represent information about which areas of the lungs are being ventilated and which are not. Second, an intravenous injection of a further gamma emitter, such as radioactive technetium macro aggregated albumin (Tc99m-MAA), is administered to the subject while recording further images of the subject's chest using the gamma camera. The resulting images show light areas wherever the gamma emitter has been carried within the lungs by the blood stream and therefore represent information about which regions of the lungs are being well perfused with blood. It will be appreciated that in some cases the resulting images are seen in negative, i.e. dark areas indicate higher concentrations of radiation emitting material as opposed to light areas as mentioned above.
The clinician, analysing the results of a V/Q scan may be interested in physiological parameters such as how well certain regions of the lungs are being ventilated with air or perfused with blood, but is often particularly interested in mismatches between the quality of ventilation and of perfusion in local regions in the lungs. Such mismatches indicate that gas transfer between the air and blood in the lungs is inefficient, because lung regions supplied with inhaled air are not being supplied with blood and/or lung regions supplied with blood are not being supplied with air. In the case of both chronic illnesses such as obstructive pulmonary disease and acute illnesses such as pulmonary embolism, V/Q scans are particularly valuable since they can be used to identify obstructions within the airways or blood vessels which are causing a ventilation/perfusion mismatch in a region of a lung. Unfortunately, V/Q scans provide relatively low resolution, two dimensional results (i.e. images). It will be appreciated that more local information, such as would be provided by volumetric data, would be extremely valuable in order to provide more detailed prognoses and targeted therapies for addressing ventilation/perfusion problems. Higher resolution imaging technologies, such as magnetic resonance imaging (MRI) or x-ray computed tomography (CT), have therefore been investigated for their applicability to imaging the lungs.
Oxygen-enhanced magnetic resonance imaging (OE-MRI) is a high resolution imaging technology which has been demonstrated in both healthy volunteers and patients with pulmonary disease as an alternative, indirect method to visualize lung ventilation. Molecular oxygen is paramagnetic and so acts as an MRI contrast agent when dissolved in water due to its effect on T1 (which is known to those skilled in the art of MRI as the longitudinal relaxation time). Another standard output parameter of MRI is R1, which is the rate of longitudinal relaxation and is therefore derivable from T1 as R1=1/T1.
Oxygen is always present in a living animal body so it is not possible to use oxygen as a contrast medium in the usual way (i.e. by assuming that all visible contrast is that which has been introduced for the purposes of the study, as is the case with nuclear medicine studies). Rather, at least one baseline measurement is made while oxygen in the lung tissues is at a first concentration, and at least one contrast measurement is made while the oxygen in the lung tissues is at a second concentration. The difference between the baseline measurement(s) and the contrast measurement(s) is then calculated. Breathing 100% oxygen results in an increase in the concentration of dissolved oxygen in the water contained within both lung tissue and blood within the lungs when compared to breathing room air (at 21% oxygen), and this can be observed in data indicating the difference between the baseline measurements and the contrast measurements. More particularly, increased concentration of dissolved oxygen produces a corresponding decrease in T1 which can be detected as a regional signal intensity increase in a T1-weighted image, denoted here as ΔT1 (thus the difference in R1 as described above is denoted ΔR1). The resulting data, ΔR1, represents the increase in dissolved oxygen concentration in the lungs.
It is possible to calculate the change in partial pressure of oxygen in a region of interest within a subject from the change in longitudinal relaxation rate ΔR1 determined by OE-MRI. An approximate average conversion factor r1 between a value of ΔR1 and a value representing the partial pressure of oxygen is r1=2.49×10−4 s−1mmHg−1 (Zaharchuk G, Martin A J, Dillon W P. “Noninvasive imaging of quantitative cerebral blood flow changes during 100% oxygen inhalation using arterial spin-labeling MR imaging.” American Journal of Neuroradiology. April 2008; 29(4):663-7). This factor can be used to convert ΔR1 measurements to partial pressures of oxygen (in units of mmHg) by dividing each of the ΔR1 values generated by an OE-MRI study by the conversion factor r1, i.e. ΔPWO2=ΔR1/r1, where ΔPWO2 is the change in partial pressure of oxygen in units of millimeters of mercury (mmHg) in tissue water. It is known to perform a plurality of scans, i.e. a “study”, on the same patient over a short time scale so as to produce a dataset which represents the change in partial pressure of oxygen in a number of local regions of interest within the subject's lungs over the period of the study.
High resolution analysis of the lungs by multiple OE-MRI scans over time is made difficult by the change in size and shape of the lungs from one image to the next due to breathing. Breath-holding has been used in some studies but in patients with lung disease this can be uncomfortable and, as a result, difficult to perform in a reproducible manner. It may also be argued that breath-holding interferes with the phenomena being assessed since it requires large static inhalations which may lead to spurious interpretation of normal breathing function. Accordingly image registration methods have been developed to correct for breathing motion before calculation of ΔR1 (e.g. see Naish et al. (2005) Magnetic Resonance in Medicine 54:464-469). Such methods allow registration of a lung outline such that data resulting from multiple scans of the same subject over time can be registered together with the result that data values relating to corresponding locations within the subject's lungs are identifiable as such. Moreover, registration of datasets between different subjects may allow comparison of lung function between the subjects in such a way that differing lung sizes and shapes are at least partially accounted for.
Each data value produced by an OE-MRI scan as described above relates to the change in partial pressure of oxygen for a single point in time. Even when a study is performed, i.e. a plurality of scans over a given time period, the results are a number of scalar data values for a plurality of time points. It is not therefore possible to directly measure desired aspects function of the lung, using such a method. If a method could be found to utilise the data values produced by an OE-MRI study so as to infer functional information about a subject then functional data could be determined at OE-MRI resolutions over the region of the lungs. This data would be extremely useful in diagnosis and prognostic estimation for people or animals.
An existing method of generating functional data about the lungs from OE-MRI data is to begin by constructing a simple, highly abstracted functional model comprising model parameters the values of which are expected to change in response to a change in lung function. The model is then “fitted” to data generated for a subject over time for a region of interest. The fitting can take many forms, but its general purpose is to apply the model to the data so as to determine values for one or more model parameters which result in the model representing the data with acceptable accuracy. The values of the model parameters which have been determined by the fitting are then used to compare lung function between subjects or between datasets acquired from the same subject over time.
Such a model is validated by gathering empirical evidence that, once fitted to data, the model provides a set of data values which have diagnostic capability. That is, the value of at least one parameter of the model changes depending on the health and/or particular diagnosis of the subject. The values produced by such a model are not, however, suitable for quantitative analysis of lung function because none of the model parameters relate directly to measurable physiological parameters. Rather, the model parameters are abstract indicators which have been arrived at by roughly approximating physiological function.